The Maintenance of Human Atrial Fibrillation Project Summary. Atrial fibrillation (AF) is the most common heart rhythm disorder, affecting 2-5 million Americans in whom it may cause skipped heart beats, dizziness, stroke and even death. Unfortunately, therapy for AF is limited. One of the major drawbacks in developing better therapy for AF is that our understanding of what causes AF (its `mechanisms') is not clear. This renewal outlines a program of career development for the applicant, of Mentored training for young clinician-scientists, and of mechanistic patient-oriented research in atrial fibrillation The Research Plan builds upon discoveries in the last cycle, that human AF is often not random, but instead maintained (driven) by a small number of `sources' in the form of rotors (akin to electrical spinning tops) or focal beats, that are stable over time. Sources may lie in regions of the heart (the atria, or top chambers) that are different in each patient, often away from where physicians currently apply cautery therapy (ablation). In this project, we will study 1) how much additional benefit is achieved by ablating at trigger sites (at the pulmonary veins) over and above these rotor source; 2) how rotors actually cause disorganized rhythms, and not just simple organized circuits; 3) whether this process is altered by structural abnormalities in the atria. We will pursue these aims in a clinical trial, by making detailed recordings of AF, usin bioengineering methods and by integrating imaging. These patient-specific analyses will be among the most detailed and clinically-relevant in the field, and will form a platform for future hypothesis testing and clinical trials. This project is significant because it tests the success of novel therapy at recently discovered AF rotors against current standard-of-care, because it studies the fundamental mechanisms that cause cardiac fibrillation in humans, and because it also tests novel imaging strategies. This project will be performed in patients with AF and a limited number of patients without AF, during electrophysiologic study, so that its results can be translated directly to practice. This approach may also allow a more rational general approach to drug development and gene therapy.